X-153694749-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005629.4(SLC6A8):c.1627G>A(p.Glu543Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,209,700 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E543Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000028 ( 0 hom. 11 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.537

Publications

1 publications found

Variant links:

Genes affected

SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

SLC6A8 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.089541465).

BP6

Variant X-153694749-G-A is Benign according to our data. Variant chrX-153694749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212212.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	NM_005629.4	MANE Select	c.1627G>A	p.Glu543Lys	missense	Exon 12 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.1597G>A	p.Glu533Lys	missense	Exon 12 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.1282G>A	p.Glu428Lys	missense	Exon 12 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1627G>A	p.Glu543Lys	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.1624G>A	p.Glu542Lys	missense	Exon 12 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1618G>A	p.Glu540Lys	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182609

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1097214

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

362958

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26374

American (AMR)

AF:

0.0000284

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54097

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3644

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

841902

Other (OTH)

AF:

0.0000217

AC:

AN:

46028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34678

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30998

American (AMR)

AF:

0.00

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2757

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53159

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine deficiency syndrome 1 (1)

Creatine transporter deficiency (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.010

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.083

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

0.54

PrimateAI

Benign

0.39

PROVEAN

Benign

0.70

REVEL

Benign

0.15

Sift

Benign

0.63

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.23

MVP

0.28

MPC

0.17

ClinPred

0.016

GERP RS

-6.8

Varity_R

0.067

gMVP

0.71

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over